Publications by authors named "Barbara Tolusso"

79 Publications

Loss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in arthritis.

Nat Commun 2021 04 20;12(1):2343. Epub 2021 Apr 20.

Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.

In healthy joints, synovial fibroblasts (SFs) provide the microenvironment required to mediate homeostasis, but these cells adopt a pathological function in rheumatoid arthritis (RA). Carbohydrates (glycans) on cell surfaces are fundamental regulators of the interactions between stromal and immune cells, but little is known about the role of the SF glycome in joint inflammation. Here we study stromal guided pathophysiology by mapping SFs glycosylation pathways. Combining transcriptomic and glycomic analysis, we show that transformation of fibroblasts into pro-inflammatory cells is associated with glycan remodeling, a process that involves TNF-dependent inhibition of the glycosyltransferase ST6Gal1 and α2-6 sialylation. SF sialylation correlates with distinct functional subsets in murine experimental arthritis and remission stages in human RA. We propose that pro-inflammatory cytokines remodel the SF-glycome, converting the synovium into an under-sialylated and highly pro-inflammatory microenvironment. These results highlight the importance of glycosylation in stromal immunology and joint inflammation.
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http://dx.doi.org/10.1038/s41467-021-22365-zDOI Listing
April 2021

Synovial tissue derived characteristics are included in a nomogram for the prediction of treatment response in naïve Rheumatoid Arthritis.

Arthritis Rheumatol 2021 Mar 22. Epub 2021 Mar 22.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Objectives: This study aims to apply the synovitis assessment in routine care of naïve Rheumatoid Arthritis (RA) and to develop a multiparametric nomogram for baseline diagnostic and treatment response prediction.

Methods: 1015 patients [545 RA, 167 Psoriatic Arthritis (PsA), 199 Undifferentiated Peripheral Inflammatory Arthritis (UPIA), 18 crystal arthritis, 26 connective tissue diseases and 60 osteoarthritis (OA)] undergoing ultrasound (US)-guided synovial tissue (ST) biopsy were enrolled (SYNGem) and stratified based on disease phase. The Krenn synovitis score(KSS) was assessed and integrated with disease characteristics and clinical outcome and a nomogram was created incorporating predictors of "DAS-Remission achievement at 6 months" in naïve RA treated with a treat to target strategy.

Results: KSS significantly differs among patients with RA, as well as PsA and UPIA, when compared to OA. In RA, KSS directly correlated with DAS28 and was related to autoantibody positivity in naïve RA. Moreover, naïve RA achieving 6 months DAS-remission had, at baseline, lower KSS, shorter symptoms duration (VERA) and lower disease activity than naïve RA not achieving DAS-remission. On logistic regression, being VERA, not having high disease activity and having a KSS<5 at baseline, were synergistic factors of DAS-remission achievement at 6 months and a nomogram integrating baseline clinical and histological characteristics of naïve RA enabled to predict up to 81.7% of probability to achieve 6 months DAS-remission.

Conclusion: KSS is a reliable tool for synovitis assessment on US-guided ST biopsies being contingent on disease phase, autoimmune profile and integrated within a therapeutic response predictive nomogram in naïve RA.
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http://dx.doi.org/10.1002/art.41726DOI Listing
March 2021

Systemic Bone Density at Disease Onset Is Associated With Joint Erosion Progression in Early Naive to Treatment Rheumatoid Arthritis: A Prospective 12-Month Follow-Up Open-Label Study.

Front Med (Lausanne) 2021 25;8:613889. Epub 2021 Feb 25.

Division of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy.

Osteoporosis and bone erosions are hallmarks of rheumatoid arthritis (RA) since disease onset is underpinned by the inflammatory burden. In this observational study, we aimed to dissect the putative RA-related parameters and bone-derived biomarkers associated with systemic and focal bone loss at disease onset and with their progression. One-hundred twenty-eight patients with early rheumatoid arthritis (ERA) were recruited at disease onset. At study entry, demographic, clinical, and immunological parameters were recorded. Each ERA patient underwent plain X-rays of the hands and feet at study entry and after 12 months to assess the presence of erosions. After enrollment, each patient was treated according to the recommendations for RA management and followed up based on a treat-to-target (T2T) strategy. At baseline, blood samples for soluble biomarkers were collected from each patient, and plasma levels of osteoprotegerin (OPG), receptor activator of nuclear factor κB ligand (RANKL), Dickkopf-1 (DKK1), and interleukin 6 (IL-6) were assessed by enzyme-linked immunosorbent assay (ELISA). Seventy-one ERA patients underwent bone mineral density (BMD) measurement at the left femoral neck and second to fourth lumbar spine vertebrae (L2-L4) by dual-energy X-ray absorptiometry (DXA). Among the whole cohort, 34 (26.6%) ERA patients with bone erosions at study entry had a higher disease activity ( = 0.02) and IL-6 plasma levels ( = 0.03) than non-erosive ones. Moreover, at DXA, 33 (46.5%) ERA patients had osteopenia, and 16 (22.5%) had osteoporosis; patients with baseline bone erosions were more likely osteopenic/osteoporotic than non-erosive ones ( = 0.03), regardless of OPG, RANKL, and DKK1 plasma levels. Obese ERA patients were less likely osteopenic/osteoporotic than normal weight ones ( = 0.002), whereas anti-citrullinated protein antibodies (ACPA) positive ERA patients were more likely osteopenic/osteoporotic than ACPA negative ones ( = 0.034). At logistic regression analysis, baseline Disease Activity Score measured on 44 joints (DAS44) [OR: 2.46 (1.11-5.44)] and osteopenic/osteoporosis status [OR: 7.13 (1.27-39.94)] arose as independent factors of erosiveness. Baseline osteopenic/osteoporotic status and ACPA positivity were associated with bone damage progression during the follow-up. Bone erosions presence is associated with systemic bone loss since the earliest phases of RA, suggesting that the inflammatory burden and autoimmune biology, underpinning RA, represent crucial enhancers of bone remodeling either locally as at systemic level.
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http://dx.doi.org/10.3389/fmed.2021.613889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959810PMC
February 2021

Rituximab Followed by Belimumab Controls Severe Lupus Nephritis and Bullous Pemphigoid in Systemic Lupus Erythematosus Refractory to Several Combination Therapies.

Front Med (Lausanne) 2020 28;7:553075. Epub 2020 Oct 28.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Systemic lupus erythematosus (SLE) and bullous pemphigoid (BP) are chronic autoimmune diseases in which B cells play an important pathogenic role in the different stages of the disease. B cell-targeted therapies have been suggested as a new rational approach for treating SLE. Rituximab (RTX), an anti-CD20 chimeric monoclonal antibody, failed to achieve primary endpoints in two clinical trials (EXPLORER and LUNAR) despite multiple observational and retrospective studies showing its beneficial effect on SLE. Moreover, RTX is recommended in cases of BP that is unresponsive to conventional treatments. Belimumab (BLM), a human immunoglobulin G1 λ monoclonal antibody that inhibits soluble B-lymphocyte stimulator (BlyS)/B-cell activating factor (BAFF), is the only biological treatment approved for standard therapy of refractory autoantibody-positive active SLE. Animal models and a few case reports have supported the efficacy of the combined use of RTX followed by BLM as maintenance therapy in severe lupus nephritis (LN), suggesting that their combined use may be more effective than their single use, without compromising safety. In this study, we describe the clinical case of a SLE patient with predominant renal involvement in overlap with BP, refractory to conventional therapy including RTX alone, achieving significant steroid sparing and clinical remission under sequential treatment of RTX-BLM. Moreover, we describe the first case of BP successfully treated with BLM. This case report may encourage further clinical research studies in B lymphocyte targeted combination therapy in patients affected by SLE with major organ involvement or with refractory disease, suggesting that RTX and BLM sequential therapy may be a valid option for the treatment of SLE manifestations, including conventional therapy and RTX-resistant LN.
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http://dx.doi.org/10.3389/fmed.2020.553075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657367PMC
October 2020

Basophil activation and serum IL-5 levels as possible monitor biomarkers in severe eosinophilic asthma patients treated with anti-IL-5 drugs.

Allergy 2020 Oct 25. Epub 2020 Oct 25.

UOC Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy.

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http://dx.doi.org/10.1111/all.14643DOI Listing
October 2020

Switching from IFX originator to biosimilar CT-P13 does not impact effectiveness,safety and immunogenicity in a large cohort of IBD patients.

Expert Opin Biol Ther 2021 Jan 31;21(1):97-104. Epub 2020 Oct 31.

CEMAD - IBD UNIT - Unità Operativa Complessa di Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario "A. Gemelli" IRCCS , Rome, Italy.

Background: Switching from IFX originator to CT-P13 is safe; however, little data on immunogenicity exists.

Research Design And Methods: Consecutive IBD patients on IFX originator were switched to CT-P13 and followed-up for 12 months. Clinical activity, infliximab trough levels (ITLs), anti-drug antibodies (ATIs), and adverse events were recorded at predefined timepoints (baseline, second CT-P13 infusion, 6 and 12 months). The outcomes investigated were immunogenicity, pharmacokinetics, effectiveness and safety.

Results: 119 patients were switched to CT-P13 after a median time with IFX of 5.8 years. No changes in mean ITLs were observed. ATIs were detected in 30 patients (25.2%): 14 before and 16 after switch. Mean persistent ATIs were significantly higher compared to mean transient ones (109.74 ng/mL ±84.70 vs 18.22 ng/mL ±11.37, p < 0.001), with significantly lower ITLs associated (mean 0.32 µg/mL ±0.6 vs 3.08 µg/mL ±3.22, p < 0.001). A significant decrease of patients in steroid-fee clinical remission was observed after the switch (p = 0.004), with subsequent improvement at 6 months (p = 0.005). Eighteen patients (15.1%) discontinued IFX, only 6 (5%) for loss of response.

Conclusions: Switching from infliximab originator to CT-P13 seems safe and effective, without differences in immunogenicity. A temporary reduction of clinical benefit after switching could be potentially explained by a 'nocebo-effect response'.
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http://dx.doi.org/10.1080/14712598.2020.1839045DOI Listing
January 2021

Sarilumab use in severe SARS-CoV-2 pneumonia.

EClinicalMedicine 2020 Oct 2;27:100553. Epub 2020 Oct 2.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Dipartimento di Scienze di Laboratorio e Infettivologiche, Rome, Italy.

Background: Interleukin-6 signal blockade showed preliminary beneficial effects in treating inflammatory response against SARS-CoV-2 leading to severe respiratory distress. Herein we describe the outcomes of off-label intravenous use of Sarilumab in severe SARS-CoV-2-related pneumonia.

Methods: 53 patients with SARS-CoV-2 severe pneumonia received intravenous Sarilumab; pulmonary function improvement or Intensive Care Unit (ICU) admission rate in medical wards, live discharge rate in ICU treated patients and safety profile were recorded. Sarilumab 400 mg was administered intravenously on day 1, with eventual additional infusion based on clinical judgement, and patients were followed for at least 14 days, unless previously discharged or dead.

Findings: Of the 53 SARS-CoV-2 patients receiving Sarilumab, 39(73·6%) were treated in medical wards [66·7% with a single infusion; median PaO/FiO:146(IQR:120-212)] while 14(26·4%) in ICU [92·6% with a second infusion; median PaO/FiO: 112(IQR:100-141.5)].Within the medical wards, 7(17·9%) required ICU admission, 4 of whom were re-admitted to the ward within 5-8 days. At 19 days median follow-up, 89·7% of medical inpatients significantly improved (46·1% after 24 h, 61·5% after 3 days), 70·6% were discharged from the hospital and 85·7% no longer needed oxygen therapy. Within patients receiving Sarilumab in ICU, 64·2% were discharged from ICU to the ward and 35·8% were still alive at the last follow-up. Overall mortality rate was 5·7%.

Interpretation: IL-6R inhibition appears to be a potential treatment strategy for severe SARS-CoV-2 pneumonia and intravenous Sarilumab seems a promising treatment approach showing, in the short term, an important clinical outcome and good safety.
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http://dx.doi.org/10.1016/j.eclinm.2020.100553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7531933PMC
October 2020

Psoriatic arthritis and depressive symptoms: does systemic inflammation play a role?

Clin Rheumatol 2021 May 3;40(5):1893-1902. Epub 2020 Oct 3.

Division of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy.

Objectives: Depression is commonly associated with psoriatic arthritis (PsA), but its risk factors in these patients are largely unrecognized. Pro-inflammatory cytokines involved in the pathogenesis of PsA have been associated with depression in patients without autoimmune diseases. The aim of this study was to establish whether PsA patients with and without depressive symptoms differed for general or clinical variables and serum cytokines milieu.

Methods: One hundred and fifty consecutive patients with PsA were screened for depressive symptoms with Hospital Anxiety and Depression Scale (HADS-D). Patients with and without depressive symptoms were compared according to the prevalence of general risk factors for depression, comorbidities, PsA features and serum IL-6, TNF-α, and IL-17A.

Results: Fifty-eight patient (38.7%) had a depressive mood. Depressive symptoms were associated with female sex (p = 0.03) and current smoking (p = 0.05). Patients with and without depressive symptoms did not differ for general risk factors for depression and comorbidities. Depressed patients had more frequently psoriatic nail disease (p = 0.02) and significant physical disability (HAQ-DI ≥ 0.5) (p < 0.01) and were more frequently in moderate or high disease activity according to DAPSA score (p = 0.01). Depressed patients had higher serum IL-6 (p < 0.01) and comparable serum IL-17A and TNF-α. A cutoff of 2.27 pg/ml of serum IL-6 had the best ability to predict an HADS-D ≥ 8 (AUC 0.666 ± 0.044; p < 0.01). Multivariate logistic regression analysis confirmed that serum IL-6 ≥ 2.27 pg/ml was independently associated with depressive symptoms (OR 3.5; CI 1.6-7.8; p < 0.01).

Conclusions: Higher serum Il-6 is associated with depressive symptoms. This association suggests a direct role of systemic inflammation in the modulation of mood in PsA patients. Key Points • High PsA disease activity and physical disability are associated with depression. • Higher serum levels of IL-6 are independently associated with depression in PsA. • IL-6 might play a direct role in the development of depression in PsA patients.
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http://dx.doi.org/10.1007/s10067-020-05417-5DOI Listing
May 2021

Basic immunology may lead to translational therapeutic rationale: SARS-CoV-2 and rheumatic diseases.

Eur J Clin Invest 2020 Sep 29;50(9):e13342. Epub 2020 Jul 29.

Division of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy.

COVID-19 pandemia is a major concern for patients and healthcare systems. The fear of infection by patients with concomitant rheumatic diseases (either adult or children) and connective tissue diseases is arising worldwide, because of their immunological background and immunological therapies. Analysing the basic biology of single diseases, the data suggest that there is an "immunological umbrella" that seems to protect against the infection, through IFN type 1 and NK cell function. To date, reports from China, United States and Europe did not reveal an higher risk of infection, either for rheumatoid arthritis, juvenile idiopathic arthritis nor for lupus erythematosus. Antimalarials, anti-IL6-Anti-IL6 receptor, anti-IL1, anti-GM-CSF receptor and JAK1/2/3 inhibitors, are under investigation in COVID-dedicated clinical trials to control the inflammation raised by SARS-CoV-2 infection. Initial reports on the occurrence of autoimmune phenomena in the convalescence phase of SARS-CoV-2 infection suggests that the immunological consequences of the infection need to be strictly understood. Reporting of the study conforms to broad EQUATOR guidelines (Simera et al January 2010 issue of EJCI).
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http://dx.doi.org/10.1111/eci.13342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7404583PMC
September 2020

Comparative analysis of synovial inflammation after SARS-CoV-2 infection.

Ann Rheum Dis 2020 Jul 6. Epub 2020 Jul 6.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore Facoltà di Medicina e Chirurgia, Roma, Italy

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http://dx.doi.org/10.1136/annrheumdis-2020-218315DOI Listing
July 2020

Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis.

Nat Med 2020 08 29;26(8):1295-1306. Epub 2020 Jun 29.

Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), .

Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKTREM2 and MerTKLYVE1) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTK STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTK STM subpopulations could therefore be a potential treatment strategy for RA.
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http://dx.doi.org/10.1038/s41591-020-0939-8DOI Listing
August 2020

Early vedolizumab trough levels predict treatment persistence over the first year in inflammatory bowel disease.

United European Gastroenterol J 2019 11 3;7(9):1189-1197. Epub 2019 Sep 3.

UOC Medicina Interna e Gastroenterologia Columbus, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Background: Data from trials of vedolizumab for inflammatory bowel disease and from real-world studies suggest an exposure-response relationship, such that vedolizumab trough levels may predict clinical and endoscopic outcomes.

Objective: The purpose of this study was to evaluate in a prospective observational study the utility of an early vedolizumab trough level assay for predicting the first-year vedolizumab therapy outcome.

Methods: This prospective observational study included consecutive inflammatory bowel disease patients. We measured vedolizumab trough levels and anti-vedolizumab antibodies at weeks 6 and 14. Clinical outcome was assessed at weeks 6, 14, 22 and 54. The primary endpoint was the correlation between early vedolizumab trough levels and vedolizumab persistence over the first year of treatment, defined as the maintenance of vedolizumab therapy due to sustained clinical benefit.

Results: We included 101 patients initiating vedolizumab. A cut-off vedolizumab trough level of 16.55 µg/ml at week 14 predicted vedolizumab persistence within the first year of therapy, with 73.3% sensitivity and 59.4% specificity ( = 0.0009). Week 14 vedolizumab trough level was significantly higher in patients with clinical remission at weeks 14, 22 and 54; and in patients achieving mucosal healing within 54 weeks.

Conclusion: High vedolizumab trough level at week 14 was associated with a higher probability of maintaining vedolizumab therapy over the first year due to sustained clinical benefit.
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http://dx.doi.org/10.1177/2050640619873784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6826518PMC
November 2019

Laboratory Monitoring of Biological Therapies in Rheumatology: The Role of Immunogenicity.

Ann Lab Med 2020 Mar;40(2):101-113

World Association of Societies of Pathology and Laboratory Medicine, Milan, Italy.

Biological drugs, such as proteins and immunogens, are increasingly used to treat various diseases, including tumors and autoimmune diseases, and biological molecules have almost completely replaced synthetic drugs in rheumatology. Although biological treatments such as anti-tumor necrosis factor (TNF) drugs seem to be quite safe, they cause some undesirable effects, such as the onset of infections due to weakening of the immune system. Given the biological nature of these drugs, they might be recognized as extraneous; this would induce an immune reaction that neutralizes their effectiveness or lead to more serious consequences. Laboratories play a pivotal role in appropriate therapeutic management. The aim of this review was to underline the production of anti-drug antibodies during treatment with biological drugs and highlight the role of laboratories in ensuring appropriate use of these drugs.
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http://dx.doi.org/10.3343/alm.2020.40.2.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822010PMC
March 2020

The B side of rheumatoid arthritis pathogenesis.

Pharmacol Res 2019 11 28;149:104465. Epub 2019 Sep 28.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy; Institute of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy. Electronic address:

In the last years, a dramatic amount of research has been performedincreasing the knowledge about the biological mechanism underpinning Rheumatoid Arthritis (RA) inflammation, putting B lymphocytes in the center of RA pathogenesis. Nowadays, B cell phenotypes and autoantibodies positivity arose as important biomarkers in early and long-standing disease. Moreover, comparative analysis of peripheral blood and synovial tissue compartments enables the identification of novel physiopathological mechanisms promoting inflammation. In this narrative review we will discuss the biological relevance of B cell derived autoimmunity and in RA course, from disease onset to remission achievement.
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http://dx.doi.org/10.1016/j.phrs.2019.104465DOI Listing
November 2019

Measuring the T-cell down-regulation of TCR-zeta, ZAP-70 and CD28 in arthritis patients: An old tool for new biomarkers.

Eur J Immunol 2019 12 22;49(12):2195-2203. Epub 2019 Aug 22.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli - Catholic University of the Sacred Heart, Rome, Italy.

Low T-cell receptor (TCR)/CD28 signaling lymphocytes are expanded in arthritis. We asked whether the down-expression of TCR-related molecules correlates with specific arthritis characteristics and if it has clinical implications. TCR-ZETA, ZAP-70 and CD28 expression was measured by flow cytometry in synovial fluid (SF) and peripheral blood (PB)-derived T cells. In PB, ZETA-downregulation in CD4 CD28 and consequent CD4 CD28lowZETAlow cell expansion correlate with CRP elevation, leukocyte recruitment into SF and, primarily, disease activity (DAS). In some patients, ZETA-downregulation extends to CD8 CD28null and/or CD8 CD28 cells, and this correlates with enhanced leukocyte recruitment, multiple joint involvement, and disability index (HAQ). ZETA-downregulation in CD4 CD28 may also lead to CD4 CD28 ZETAnull cell expansion, which strongly correlates with HAQ. In SF, ZETA-downregulation in CD8 CD28null and consequent CD8 CD28nullZETAlow/null cell expansion correlate with CRP elevation and neutrophilic influx into SF, whereas ZAP-downregulation in CD8 CD28 and consequent CD8 CD28lowZAPlow cell expansion strongly correlate with HAQ and DAS. ZETA-downregulation is preponderant in SF of seronegative arthritides, with seronegative rheumatoid arthritis showing significant down-regulation in CD8 CD28null, and non-rheumatoid arthritides showing significant down-regulation in CD4 CD28 . Altogether, we identified new molecular and cellular biomarkers of arthritis-related T-cell inflammation, useful for assessing arthritis activity, predicting polyarticular progression and functional impairment, characterizing seronegative arthritides, and possibly tailoring immunotherapies.
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http://dx.doi.org/10.1002/eji.201847849DOI Listing
December 2019

Overweight/obesity affects histological features and inflammatory gene signature of synovial membrane of Rheumatoid Arthritis.

Sci Rep 2019 07 18;9(1):10420. Epub 2019 Jul 18.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Overweight/obesity influence disease burden and clinical outcome of Rheumatoid Arthritis (RA). The impact of overweight/obesity on synovial tissue (ST) inflammation is largely unknown. Here, we investigated the histological and transcriptional signature of ST obtained from RA in different disease phases (disease onset, failure to first-line conventional DMARDs and in sustained clinical and ultrasound remission) finding that overweight/obese DMARDs naive RA showed higher likelihood of follicular synovitis, higher IHC scores for sublining inflammatory cells (CD68, CD21 and CD20) and higher IL-1RA plasma levels than normal weight RA. Regardless to the synovitis pattern, overweight/obese DMARDs naive RA showed a worse clinical response to "Treat-to-target" (T2T) than normal weight RA at 6 and 12 months follow-up. Conversely, MTX-IR RA did not show significant differences in synovial inflammation based on BMI category. Overweight/obese RA in stable clinical and US remission showed higher degree of residual synovitis in terms of sublining CD68, CD20 cells and lining and sublining CD3 compared to normal weight RA. Finally, gene expression profile analysis revealed that ST of overweight/obese DMARDs naive RA is enriched by CCL3 and MyD88 compared to normal weight RA in sustained disease remission, the latter correlating with BMI and IHC scores for synovial CD68 cells. These findings suggest that indeed overweight/obese RA show higher degree of synovitis at disease onset and after remission achievement that influences the response rate to T2T and should be considered within the management of patients with RA.
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http://dx.doi.org/10.1038/s41598-019-46927-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639364PMC
July 2019

JAK inhibition by methotrexate (and csDMARDs) may explain clinical efficacy as monotherapy and combination therapy.

J Leukoc Biol 2019 11 16;106(5):1063-1068. Epub 2019 Jul 16.

Institute of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy.

Methotrexate (MTX) is recognized as the anchor drug in the algorithm treating chronic arthritis (RA, psoriatic arthritis), as well as a steroid sparing agent in other inflammatory conditions (polymyalgia rheumatica, vasculitis, scleroderma). Its main mechanism of action has been related to the increase in extracellular adenosine, which leads to the effects of A2 receptor in M1 macrophages that dampens TNFα and IL12 production and increases IL1Ra and TNFRp75. By acting on A2 receptor on M2 macrophages it enhances IL10 synthesis and inhibits NF-kB signaling. MTX has also been shown to exert JAK inhibition of JAK2 and JAK1 when tested in Drosophila melanogaster as a model of kinase activity and in human cell lines (nodular sclerosis Hodgkin's lymphoma and acute myeloid leukemia cell lines). These effects may explain why MTX leads to clinical effects similar to anti-TNFα biologics in monotherapy, but is less effective when compared to anti-IL6R in monotherapy, which acting upstream exerts major effects downstream on the JAK1-STAT3 pathway. The MTX effects on JAK1/JAK2 inhibition also allows to understand why the combination of MTX with Leflunomide, or JAK1/JAK3 inhibitor leads to better clinical outcomes than monotherapy, while the combination with JAK1/JAK2 or JAK1 specific inhibitors does not seem to exert additive clinical benefit.
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http://dx.doi.org/10.1002/JLB.5RU0519-145RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852123PMC
November 2019

Differential synovial tissue biomarkers among psoriatic arthritis and rheumatoid factor/anti-citrulline antibody-negative rheumatoid arthritis.

Arthritis Res Ther 2019 05 9;21(1):116. Epub 2019 May 9.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Background: Differential diagnosis among psoriatic arthritis (PsA) and seronegative rheumatoid arthritis (Ab RA) can be challenging particularly in the clinical setting of peripheral phenotype and autoantibodies seronegativity. The aim of the study was to identify synovial tissue (ST) biomarkers differentially expressed in PsA and Ab RA and test their predictive value of therapeutic response.

Methods: Thirty-four PsA patients [12 DMARD naive and 22 non-responder to methotrexate (MTX-IR)] with peripheral joint involvement and 55 Ab RA (27 DMARD naive and 28 MTX-IR) underwent US-guided ST biopsy and immunohistochemistry (IHC) for CD68, CD3, CD20, CD21, CD117, and CD138 cells. After study entry, each DMARD-naive patient started MTX therapy and was followed in an outpatient setting for at least 6 months to define the achievement of Minimal Disease Activity (PsA) and DAS remission (Ab RA) status respectively. Each IR-MTX patient was treated according to EULAR recommendations.

Results: At study entry, IHC analysis revealed that PsA patients had comparable levels of lining and sublining CD68 and sublining CD21, CD20, and CD3 cells than Ab RA, despite the therapeutic regimen. Moreover, regardless of the therapeutic scheme, PsA patients showed higher IHC score of CD117 cells (p = 0.0004 and p = 0.0005 for naive and MTX-IR patients respectively) compared to Ab RA patients. Conversely, Ab RA patients showed higher IHC score of CD138 cells, irrespective to the therapeutic scheme (p = 0.04 and p = 0.002 for naive and MTX-IR patients respectively). Analyzing the response rate to the therapeutic scheme, naive PsA patients reaching MDA status at 6 months follow-up, showed, at the study entry, lower IHC score of CD3 cells compared to PsA patients not reaching this outcome (p = 0.02); conversely, naive Ab RA patients reaching DAS remission status at 6 months follow-up, showed, at the study entry, lower IHC score of sublining CD68 cells compared to Ab RA patients not reaching this outcome (p < 0.001).

Conclusions: CD117 and CD138 cells are differentially distributed among PsA and Ab RA. Histological analysis of ST may help to solve the clinical overlap between the two diseases and provides prognostic data about the therapy success.
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http://dx.doi.org/10.1186/s13075-019-1898-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509792PMC
May 2019

Amplifying the concept of psoriatic arthritis: The role of autoimmunity in systemic psoriatic disease.

Autoimmun Rev 2019 Jun 5;18(6):565-575. Epub 2019 Apr 5.

Rheumatology, Allergology and Clinical Immunology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis that may be present in near 30% of patients affected by psoriasis (PsO), clinically characterized by inflammation of periarticular (e.g., enthesis) and articular structures. Recently, an autoimmune footprint of PsA pathogenesis has been demonstrated with the presence of autoantigens and related autoantibodies in PsA patients' sera. In this context, histological features of PsA synovitis supports the relevance of an autoimmune pathogenesis of the disease. Since there is no currently validated test for PsA, the analysis of PsA synovial tissue revealed pathognomonic characteristics of PsA that may support the clinician in the clinical practice. PsA synovitis is characterized by a sublining infiltrate with T and B cells, vascular proliferation and a relative thin lining layer of proliferating intimal synoviocytes. PsA synovial histopathology shows that ectopic lymphoid-neogenesis with an increase of IL-23 expression. These new pathogenetics features and the systemic nature of the disease raised the concept of a Systemic Psoriatic Disease (SysPsD), characterized by multiple extra-cutaneous and -articular manifestations, highlightening the great heterogeneity of this condition. SyPsD represents a heterogeneous chronic inflammatory condition with a wide spectrum of phenotypical manifestations. The purpose of this review is to describe the new pathogenetic mechanisms and the different clinical pictures of SysPsD, with the ultimate goal of improving the knowledge of this heterogeneous chronic inflammatory condition.
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http://dx.doi.org/10.1016/j.autrev.2018.11.007DOI Listing
June 2019

Comment on: Emergence of severe spondyloarthropathy-related entheseal pathology following successful vedolizumab therapy for inflammatory bowel disease.

Rheumatology (Oxford) 2019 06;58(6):1113-1115

IBD Unit, Presidio Columbus, Division of Gastroenterology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italia.

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http://dx.doi.org/10.1093/rheumatology/kez056DOI Listing
June 2019

Correction to: Anti-Müllerian hormone serum levels in systemic lupus erythematosus patients: influence of the disease severity and therapy on the ovarian reserve.

Endocrine 2019 Feb;63(2):405

Institute of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy.

The original version of this article unfortunately contained a mistake in given and family names of all the authors.
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http://dx.doi.org/10.1007/s12020-018-1811-1DOI Listing
February 2019

Anti-Müllerian hormone serum levels in systemic lupus erythematosus patients: Influence of the disease severity and therapy on the ovarian reserve.

Endocrine 2019 02 15;63(2):369-375. Epub 2018 Oct 15.

Institute of Rheumatology, Università Cattolica del Sacro Cuore, Rome, Italy.

Purpose: Systemic lupus erythematosus (SLE) mainly affects childbearing age women and pharmacological treatments may negatively influence the ovarian reserve. Anti-Müllerian hormone (AMH) could be a good biomarker for ovarian reserve.

Methods: AMH serum levels were assessed in 86 consecutive SLE female patients with regular menstrual cycle compared with 44 aged matched healthy controls. Clinical and demographic characteristics, disease duration, pattern of organ involvement, and previous and current therapies were recorded.

Results: AMH levels were comparable between patients and controls (4.2 ± 3.1 ng/ml vs. 5.0 ± 3.1 ng/ml, p = 0.21). According to disease severity, AMH levels were lower in SLE patients with major organ involvement than in controls (3.8 ± 2.7 ng/ml vs. 5.0 ± 3.1 ng/ml, p = 0.08); no difference was found between SLE patients with mild organ involvement (4.5 ± 3.4 ng/ml) and controls (p = 0.43). Grouping patients based on the pharmacological treatments, AMH serum levels did not differ among SLE patients treated with antimalarials only (4.7 ± 3.3 ng/ml), conventional disease-modifying antirheumatic drugs (cDMARDs) only (4.8 ± 3.2 ng/ml), cDMARDs and antimalarials (3.9 ± 2.9 ng/ml) or cyclophosphamide (CYC) only (4.9 ± 3.9 ng/ml), compared to controls, but patients sequentially treated with cDMARDs and CYC, had significantly lower AMH serum levels than controls (p = 0.01).

Conclusions: SLE patients showed comparable AMH levels than controls, however, a reduction of the ovarian reserve was associated with sequentially therapy with CYC and cDMARDs and with the disease severity. AMH could be a sensitive and specific biomarker of ovarian reserve in SLE and it could be useful for therapeutic strategy and family planning.
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http://dx.doi.org/10.1007/s12020-018-1783-1DOI Listing
February 2019

Anti-LL37 Antibodies Are Present in Psoriatic Arthritis (PsA) Patients: New Biomarkers in PsA.

Front Immunol 2018 12;9:1936. Epub 2018 Sep 12.

Istituto Superiore di Sanità, National Center for Drug Research and Evaluation, Rome, Italy.

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis. A third of psoriatic patients develop PsA unknown mechanisms. No reliable diagnostic markers are available for PsA, or prognostic biomarkers for PsA development in psoriasis. We previously uncovered a pro-inflammatory role for cathelicidin LL37 in lesional psoriasis skin. LL37 binds nucleic acids and stimulates plasmacytoid/myeloid dendritic cells (pDC, mDCs) to secrete type I interferon (IFN-I) and pro-inflammatory factors. LL37 becomes an autoantigen for psoriatic Th1-Th17/CD8 T cells. Anti-LL37 antibodies were detected in systemic lupus erythematosus, an autoimmune disease characterized by neutrophil-extracellular-traps release (NETosis) in target organs. LL37 can be substrate of irreversible post-translational modifications, citrullination or carbamylation, linked to neutrophil activity. Here we analyzed inflammatory factors, included LL37, in PsA and psoriasis plasma and PsA synovial fluids (SF)/biopsies. We show that LL37 (as a product of infiltrating neutrophils) and autoantibodies to LL37 are elevated in PsA, but not OA SF. Anti-LL37 antibodies correlate with clinical inflammatory markers. Anti-carbamylated/citrullinated-LL37 antibodies are present in PsA SF/plasma and, at lower extent, in psoriasis plasma, but not in controls. Plasma anti-carbamylated-LL37 antibodies correlate with PsA (DAS44) but not psoriasis (PASI) disease activity. Ectopic lymphoid structures, and deposition of immunoglobulin-(Ig)G-complexes (IC) co-localizing with infiltrating neutrophils, are observed in PsA and not OA synovial tissues (ST). Activated complement (C5a, C9), GM-CSF and IFN-I are up-regulated in PsA and not OA synovia and in PsA and psoriasis plasma but not in HD. C9 and GM-CSF levels in PsA SF correlate with clinical inflammatory markers and DAS44 (C9) and with anti-carbamylated/citrullinated-LL37 antibodies (GM-CSF and IFN-I). Thus, we uncover a role for LL37 as a novel PsA autoantibody target and correlation studies suggest participation of anti-LL37 antibodies to PsA pathogenesis. Notably, plasma antibodies to carbamylated-LL37, which correlate with DAS44, suggest their use as new disease activity markers. GM-CSF and complement C5a and C9 elevation may be responsible for autoantigens release by neutrophils and their modification, fueling inflammation and autoreactivity establishment. Finally, targeting GM-CSF, C5a, C9 can be beneficial in PsA.
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http://dx.doi.org/10.3389/fimmu.2018.01936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6154218PMC
September 2019

Chemerin and PEDF Are Metaflammation-Related Biomarkers of Disease Activity and Obesity in Rheumatoid Arthritis.

Front Med (Lausanne) 2018 3;5:207. Epub 2018 Aug 3.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Catholic University of the Sacred Heart, Rome, Italy.

Obesity is a risk factor for Rheumatoid Arthritis (RA) being associated to low grade inflammation. This study aimed to determine whether PEDF and Chemerin are biomarkers of inflammation related to fat accumulation in RA and to investigate whether weight loss associates with clinical disease improvement through the modification of fat-related biomarkers in overweight/obese RA with low-moderate disease. Two-hundred and thirty RA patients were enrolled, of whom 176 at disease onset treated according to a treat-to-target strategy (T2T) and 54 overweight/obese RA in stable therapy and low-moderate disease activity. Gene expression of adipokines, interleukin-6 and their receptors were examined in adipose tissue from obese RA. Obese RA with low-moderate disease activity underwent low-calories diet aiming to Body Mass Index (BMI) reduction >5%, maintaining RA therapy unchanged. Chemerin, PEDF and Interleukin-6 plasma values were assessed by ELISA and disease activity was evaluated. At RA onset, PEDF and Chemerin plasma values correlated with BMI ( < 0.001) but only Chemerin plasma values correlated with disease activity ( < 0.001). After adopting a T2T strategy, Chemerin arose as an independent factor associated with remission in early RA [OR(95%CIs):0.49(0.25-0.97)]. Moreover, after low-calories diet, RA with low-moderate disease activity reaching BMI reduction ≥5% (62.6%) at 6 months had significant decrease of PEDF ( < 0.05) and Chemerin ( < 0.05) plasma values, in parallel with the improvement in disease activity. PEDF and Chemerin arose as biomarkers of obesity and metaflammation respectively, providing a link between chronic inflammation and excess of body weight in RA. Therefore, BMI reduction of at least 5% in obese RA allowed better disease control without modifying RA treatment.
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http://dx.doi.org/10.3389/fmed.2018.00207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6085446PMC
August 2018

Synovial Predictors of Differentiation to Definite Arthritis in Patients With Seronegative Undifferentiated Peripheral Inflammatory Arthritis: microRNA Signature, Histological, and Ultrasound Features.

Front Med (Lausanne) 2018 3;5:186. Epub 2018 Jul 3.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, Catholic University of the Sacred Heart, Rome, Italy.

To examine synovial tissue (ST) predictors of clinical differentiation in patients with seronegative undifferentiated peripheral inflammatory arthritis (UPIA). Fourty-two patients with IgA/IgM-Rheumatoid Factor and anti-citrullinated peptide antibodies negative UPIA, naive to Disease-Modifying Anti-Rheumatic Drugs, underwent Gray Scale (GSUS) and power Doppler (PDUS) evaluation and Ultrasound (US) guided ST biopsy. CD68, CD3, CD21, CD20, and CD31 synovial expression was evaluated by immunohistochemistry. Whole ST microRNA expression was assessed using miScript miRNA PCR Array. Peripheral blood (PB) and synovial fluid (SF) IL-6, VEGF-A, and VEGF-D levels were measured by ELISA and ST TNF expression was assessed by RT-PCR. Each patient was prospectively monitored and classified at baseline and within 1 year as UPIA, Rheumatoid Arthritis (RA), Spondyloarthritis (SpA) or Psoriatic Arthritis (PsA), respectively. At baseline, CD68 cells were the most common cells within the lining layer ( < 0.001) in seronegative UPIA, directly correlating with GSUS ( = 0.36; = 0.02) and PDUS ( = 0.55; < 0.001). Synovial CD31 vessels count directly correlated with GSUS ( = 0.41; = 0.01) and PDUS ( = 0.52; < 0.001). During the follow-up, 6 (14.3%) UPIA reached a definite diagnosis (2 RA, 2 SpA and 2 PsA, respectively). At baseline, UPIA who differentiated had higher GSUS ( = 0.01), PDUS scores ( = 0.02) and higher histological scores for CD68 ( = 0.005 and = 0.04 for lining and sublining respectively), sublining CD3 cells ( = 0.002), CD31 vessels count ( < 0.001) and higher IL-6 PB levels ( = 0.01) than patients who remained as UPIA. MiRNA PCR Array showed that among the 86 tested miRNA species, at baseline, miR-346 and miR-214 were significantly down-regulated ( = 0.02 for both) in ST of UPIA who differentiated than in patients who remained as UPIA, inversely correlating with the lining CD68 cells IHC score ( = -0.641; = 0.048) and CD31 vessels count ( = -0.665; = 0.036) and with higher baseline ST expression of TNF ( = 0.014). Finally, logistic regression analysis demonstrated that baseline GSUS and PDUS scores ≥1.5 [OR:22.93 (95%CI:0.98-534.30)] and CD31 vessels count ≥24.3 [OR:23.66 (95%CI:1.50-373.02)] were independent factors associated with the development of definite arthritis. MiRNA signature, histological and US features of ST may help in the identification of seronegative UPIA with high likelihood of clinical differentiation toward definite seronegative arthritis.
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http://dx.doi.org/10.3389/fmed.2018.00186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6037719PMC
July 2018

Therapeutic Drug Monitoring is More Cost-Effective than a Clinically Based Approach in the Management of Loss of Response to Infliximab in Inflammatory Bowel Disease: An Observational Multicentre Study.

J Crohns Colitis 2018 08;12(9):1079-1088

OU Internal Medicine and Gastroenterology Columbus, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Background And Aims: Empirical dose intensification and therapeutic drug monitoring [TDM] of infliximab [IFX] trough levels [ITLs] and antibody to infliximab [ATI] assays are recognized approaches for managing loss of response [LoR] in patients with inflammatory bowel disease [IBD]. The aim of the study was to compare these two interventions in a clinical setting, in terms of effectiveness and cost savings.

Methods: Consecutive IBD patients experiencing LoR were clinically managed according to a TDM algorithm. A historical group of empirically treated patients, for whom sera for ITLs and ATI assays had been collected, served as the control group. Clinical outcomes 12 weeks after the therapeutic interventions were compared between the two groups. A cost-minimization analysis was performed to compare the economic impact of these two approaches.

Results: Ninety-six patients were enrolled prospectively and compared with 52 controls. The two cohorts were similar in characteristics and in the distribution of TDM results. In the prospective cohort, however, we observed less IFX dose escalations compared with in the controls [45% versus 71%, p = 0.003]. Also, more patients were switched to a different anti-TNFα in the prospective cohort than in the control cohort [25% versus 4%, p = 0.001]. The percentages of patients achieving a clinical response at 12 weeks were 52% and 54% for the prospective and control groups, respectively. By cost analysis, we estimated a savings of 15% if the TDM algorithm was applied.

Conclusions: In our population, applying a TDM algorithm for LoR to IFX resulted in less dose escalations, without loss of efficacy, compared with empirical adjustment. In addition, the TDM approach was cost-effective.
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http://dx.doi.org/10.1093/ecco-jcc/jjy076DOI Listing
August 2018

Characterization of inflammatory cell infiltrate of scleroderma skin: B cells and skin score progression.

Arthritis Res Ther 2018 04 18;20(1):75. Epub 2018 Apr 18.

Unità Operativa Complessa di Reumatologia, Istituto di Reumatologia e Scienze Affini, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: The purpose of this study was to investigate the frequency and the distribution of inflammatory cell infiltrate in two sets of cutaneous biopsies derived from clinically affected and unaffected skin in patients with systemic sclerosis (SSc) and to test correlation between the cell infiltrate and the progression of skin involvement.

Methods: Skin was immunohistochemically assessed to identify CD68, CD3, CD20 and CD138-positive (+) cells in clinically affected and unaffected skin in 28 patients with SSc. Patients were followed for 6 months and the characteristics of the infiltrate were analyzed according to disease duration, clinical features and skin involvement progression.

Results: In all SSc cutaneous specimens, cellular infiltrates were found in a perivascular location predominantly in the mid and deeper portions of the dermis. All the analyzed biopsies showed a CD3 and CD68 cell infiltrate and the mean number of CD3 and of CD68 cells was higher in clinically involved skin (CD3, 71.7 ± 34.6 and CD68, 26.3 ± 8.4, respectively) than in clinically uninvolved skin (CD3, 45.7 ± 36.0 and CD68, 13.6 ± 6.1, respectively) (p < 0.001 for both comparisons). CD20 cells were found in 17 (60.7%) patients and in these patients the mean number of CD20 cells was higher in clinically involved (4.7 ± 5.9) than in uninvolved skin (1.9 ± 2.9), (p = 0.04). There was a greater number of CD20 cells in patients with early SSc compared with patients with long-standing disease. CD138 cells were found in 100% of biopsies of clinically involved skin and in 89.3% of biopsies of uninvolved skin. The mean number of CD138 cells was higher in clinically involved skin (3.6 ± 2.3) than in clinically uninvolved skin (1.9 ± 1.7), (p < 0.001). Seven patients experienced more than 20% worsening in the skin score after 6 months of follow up; all of them had a CD20 skin infiltrate on biopsy of clinically involved skin.

Conclusions: Our results confirm that mononuclear cells are present in the skin of all patients with SSc, underlining the role of inflammatory cell infiltrates in skin involvement in SSc. B cells in the skin seem to characterize patients with early diffuse skin disease and to correlate with skin progression.
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http://dx.doi.org/10.1186/s13075-018-1569-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5907298PMC
April 2018

Paradoxical arthritis occurring during anti-TNF in patients with inflammatory bowel disease: histological and immunological features of a complex synovitis.

RMD Open 2018 9;4(1):e000667. Epub 2018 Apr 9.

Division of Rheumatology, Fondazione Policlinico Universitario A. Gemelli, Catholic University of the Sacred Heart, Rome, Italy.

Objective: Paradoxical arthritis under tumour necrosis factor inhibitor (TNF-i) for inflammatory bowel disease (IBD) has been described. This study aims to evaluate the histological features of paired synovial tissue (ST) and colonic mucosa (CM) tissue in patients with IBD developing paradoxical arthritis under TNF-i.

Methods: Patients with IBD without history of coexisting joint involvement who developed arthritis under TNF-i were enrolled. Each patient underwent ST biopsy and ileocolonoscopy with CM biopsies. ST and CM paired samples were stained through immunohistochemistry (IHC) for CD68, CD21, CD20, CD3 and CD117. Clinical and immunological parameters (anticitrullinated peptides antibodies (ACPA)-immunoglobulin (Ig)M/IgA rheumatoid factor (RF)) were collected. Psoriatic arthritis (PsA) and ACPA/IgM-RF/IgA-RF negative rheumatoid arthritis (RA) were enrolled as comparison.

Results: 10 patients with IBD (age 46.0±9.7 years, 13.2±9.9 years of disease duration, 2.5±1.6 years of TNF-i exposure, six with Crohn's disease and four with ulcerative colitis, respectively) were studied. At ST level, IHC revealed that patients with IBD with paradoxical arthritis showed more similar histological findings in terms of synovial CD68, CD21, CD20, CD3 and CD117 cells compared with PsA than ACPA/IgM-RF/IgA-RF negative RA. Analysing the CM specimens, patients with IBD showed the presence of CD68, CD3, CD117 and CD20 cells in 100%, 70%, 60% and 50% of cases, respectively, despite endoscopic remission. Finally, addition of conventional disease-modifying antirheumatic drugs and switch to ustekinumab were more effective than swapping into different TNF-i in patients with IBD with paradoxical arthritis.

Conclusion: Patients with IBD may develop histologically proven synovitis during TNF-i, comparable to PsA. The inhibition of inflammatory pathways alternative to TNF (IL12/1L23) may be an effective therapeutic option for severe paradoxical articular manifestations.
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http://dx.doi.org/10.1136/rmdopen-2018-000667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892785PMC
April 2018